Methylmercury (MeHg) exposure during gestation causes perseverative responding, impaired acquisition of choice, impulsivity, and other markers of impaired cortical function. These effects appear in adulthood and aging in animal models in which no overt toxicity is present and occurs at environmentally relevant exposures. Moreover, the effects are reversible with experience and early developmental is an especially sensitive window of exposure. Together, these observations raise the possibility that MeHg's developmental neurotoxicity is mediated by epigenetic changes in the brain. Adolescence is a life stage that is sensitive to events that disrupt cortical development and those that also have epigenetic consequences, but we know very little about MeHg exposure during this potentially vulnerable developmental period. Under Aim 1, the behavioral and epigenetic consequences of gestational MeHg exposure will be examined in a mouse model. Whole genome analyses will be conducted from prefrontal cortex in adult mice exposed to MeHg during gestation via maternal drinking water. Analyses will focus on RNA, methylation, and acetylation and will identify candidate genes for further study. Additional mice will be exposed similarly and exposed to one of three interventions designed to investigate the reversibility of MeHg-induced behavioral and epigenetic disturbances: Paired- housing (Control group), environmental enrichment, and administration of a histone deacetylation (HDAC) inhibitor, Na-butyrate. The mice will be examined on a Spatial Discrimination Reversal procedure as adults to determine the behavioral impact of these rescue attempts, after which the expression of candidate genes identified in the whole epigenome analysis will be examined. Under Aim 2, adolescent MeHg exposure will be examined in studies that otherwise mirror those conducted under Aim 1. The proposed studies will advance our understanding of the behavioral epigenetic consequences of developmental MeHg exposure, the relative vulnerability of two important exposure windows, and the potential for rescue by enrichment or HDAC inhibition.